Changes of tight junctions induced by extracellular stimuli determine cell shape and fate.

• Project/Area Number: 16K08693
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: SAWADA NORIMASA 札幌医科大学, 医学部, 教授 (30154149)
• Co-Investigator(Kenkyū-buntansha): 村田 雅樹 札幌医科大学, 医学部, 講師 (10404592)
• Research Collaborator: TAKASAWA KUMI ; AKIMOTO TAISHI
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: タイト結合 / JAM-A / claudin / occludin / tricellulin / claudin-18 / シグナル伝達 / 造腫瘍性 / フェンス機能 / 細胞ストレス / 上皮細胞接着 / “タイト結合病”

Outline of Final Research Achievements

The tight junction (TJ) is an intercellular junction that works as a barrier to external stimulation and as a fence to maintain cell polarity. Recently, aberrant expression of TJ proteins have been reported in various diseases. In this study, we focused mainly on aberrant expression in human tumor and clarified the following. TJ proteins could be diagnostic markers for some tumors including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, lung adenocarcinoma, cervical adenocarcinoma and salivary gland tumors. These findings suggested that TJ proteins are promising targets of cancer therapy. Furthermore, the expression of TJ proteins were involved in the enhancement of the malignancy of carcinoma such as invasion and proliferation. These findings suggested that abnormality of TJ might be involved in tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

ヒト癌における細胞間接着装置タイト結合の構成分子の役割を検討し、膵癌ではtricellulin、肺癌ではJAM-A、胆管癌ではclaudin-18が、癌の進行に関与していること、子宮頚部腺癌ではclaudin-1が予後不良因子でGRP30を介してエストロゲン依存性に発現していることを明らかにした。これらは、各タイト結合分子が診断マーカー又は治療標的分子となりうることを意味し、急増する種々の癌に対する新しい治療戦略を提案するもので、社会的影響や意義は大きい。

Research Products

• [Journal Article] Immunoreactivity patterns of tight junction proteins are useful for differential diagnosis of human salivary gland tumors. (2019)
  • Author(s): Aoyama T, Takasawa A, Murata M, Osanai M, Takano K, Hasegawa T, Sawada N
  • Journal Title: Med Mol Morphol. Volume: 52 Pages: 23-35
  • DOI: 10.1007/s00795-018-0199-6
  • Peer Reviewed
• [Journal Article] Identification of Coiled-Coil Domain-Containing Protein 180 and Leucine-Rich Repeat-Containing Protein 4 as Potential Immunohistochemical Markers for Liposarcoma Based on Proteomic Analysis Using Formalin-Fixed, Paraffin-Embedded Tissue. (2019)
  • Author(s): Aoyama T, Takasawa A, Takasawa K, Ono Y, Emori M, Murata M, Hayasaka T, Fujitani N, Osanai M, Yamashita T, Hasegawa T, Sawada N.
  • Journal Title: Am J Pathol Volume: in press
  • DOI: 10.1016/j.ajpath.2019.01.013
  • Peer Reviewed
• [Journal Article] Retinoic acid-metabolizing enzyme cytochrome P450 26A1 promotes skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene. (2018)
  • Author(s): Osanai M, Takasawa A, Takasawa K, Murata M, Sawada N
  • Journal Title: Oncol Lett. Volume: 15 Pages: 9987-9993
  • DOI: 10.3892/ol.2018.8599
  • Peer Reviewed / Open Access
• [Journal Article] Cytotoxicity of Clostridium perfringens enterotoxin depends on the conditions of claudin-4 in ovarian carcinoma cells. (2018)
  • Author(s): Tanaka S, Aoyama T, Ogawa M, Takasawa A, Murata M, Osanai M, Saito T, Sawada N
  • Journal Title: Experimental Cell Research Volume: 371 Pages: 278-286
  • DOI: 10.1016/j.yexcr.2018.08.024
  • Peer Reviewed
• [Journal Article] Estrogen/GPR30 Signaling Contributes to the Malignant Potentials of ER-Negative Cervical Adenocarcinoma via Regulation of Claudin-1 Expression. (2018)
  • Author(s): Akimoto T, Takasawa A, Takasawa K, Aoyama T, Murata M, Osanai M, Saito T, Sawada N
  • Journal Title: Neoplasia Volume: 10 Pages: 1083-1093
  • DOI: 10.1016/j.neo.2018.08.010
  • Peer Reviewed / Open Access
• [Journal Article] Occludin induces microvillus formation via phosphorylation of ezrin in a mouse hepatic cell line (2018)
  • Author(s): Ueda A, Takasawa A, Akimoto T, Takasawa K, Aoyama T, Ino Y, Nojima M, Ono Y, Murata M, Osanai M, Hasegawa T, Saito T, Sawada N.
  • Journal Title: Exp Cell Res. Volume: 12(8) Pages: 172-180
  • DOI: 10.1016/j.yexcr.2018.03.018
  • Peer Reviewed
• [Journal Article] Claudins in cancer: bench to bedside. (2017)
  • Author(s): Makoto Osanai, Akira Takasawa, Masaki Murata, Norimasa Sawada
  • Journal Title: Pflugers Arch Eur J Physiol. Volume: - Pages: 55-67
  • DOI: 10.1007/s00424-016-1877-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Surfactant protein A (SP-A) and SP-A-derived peptide attenuate chemotaxis of mast cells induced by human β-defensin 3 (2017)
  • Author(s): Uehara Y., Takahashi M., Murata M., Saito A., Takamiya R., Hasegawa Y., Kuronuma K., Chiba H., Hashimoto J., Sawada N., Takahashi H., Kuroki Y., Ariki S.
  • Journal Title: Biochem Biophys Res Commun Volume: 485 Pages: 107-112
  • DOI: 10.1016/j.bbrc.2017.02.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Surfactant Protein A Inhibits Growth and Adherence of UropathogenicEscherichia coliTo Protect the Bladder from Infection (2017)
  • Author(s): Hashimoto J., Takahashi M., Satio A., Murata M., Kurimura Y., Nishitani C., Takamiya R., Uehara Y., Hasegawa Y., Hiyama Y., Sawada N., Takahashi S., Masumori N., Kuroki Y., Ariki S.
  • Journal Title: Journal of immunology Volume: 198 Pages: 2898-2905
  • DOI: 10.4049/jimmunol.1502626
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cytological findings of langerhans cell sarcoma in a case of quintuple cancer. (2017)
  • Author(s): Tabata S, Murata M, Takasawa A, Fukuda A, Ogasawara J, Koseki T, Nakano K, Segawa K, Morita R, Hasegawa T, Sawada N.
  • Journal Title: Diagn Cytopathol. Volume: 45(5) Pages: 441-445
  • DOI: 10.1002/dc.23628
  • Peer Reviewed / Open Access
• [Journal Article] Caludin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer (2017)
  • Author(s): Takasawa K, Takasawa A, Osanai M, Aoyama T, Ono Y, Kono T, Hirohashi Y, Murata M, Sawada N.
  • Journal Title: Cancer Lett Volume: 403 Pages: 66-73
  • DOI: 10.1016/j.canlet.2017.05.033
  • Peer Reviewed
• [Journal Article] Elevated expression of JAM-A promotes neoplastic properties of lung adenocarcinoma (2017)
  • Author(s): Magara K, Takasawa A, Osanai M, Ota M, Tagami Y, Ono Y, Takasawa K, Murata M, Hirohashi Y, Miyajima M, Yamada G, Hasegawa T, Sawada N.
  • Journal Title: Cancer Science Volume: 108(11) Pages: 2306-2314
  • DOI: 10.1111/cas.13385
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of the expression and localization of tight junction transmembrane proteins, claudin-1, -4, -7, occludin and JAM-A, in human cervical adenocarcinoma. (2016)
  • Author(s): Akimoto T, Takasawa A, Murata M, Kojima Y, Takasawa K, Nojima M, Aoyama T, Hiratsuka Y, Ono Y, Tanaka S, Osanai M,Hasegawa T, Saito T, Sawada N.
  • Journal Title: Histol Histopathol Volume: 31(8) Pages: 921-931
  • Peer Reviewed
• [Journal Article] Increased expressions of claudin 4 and 7in atypical adenomatous hyperplasia and adenocarcinoma of the lung. (2016)
  • Author(s): Yamada G, Murata M, Takasawa A, Nojima M, Mori Y, Sawada N, Takahashi H.
  • Journal Title: Med Mol Morphol Volume: 49(3) Pages: 163-169
  • DOI: 10.1007/s00795-016-0135-6
  • Peer Reviewed
• [Journal Article] Claudins-4 and -7 might be valuable markers to distinguish hepatocellular carcinoma from cholangiocarcinoma. (2016)
  • Author(s): Yusuke Ono, Yutaro Hiratsuka, Masaki Murata, Akira Takasawa, Rieko Fukuda, Masanori Nojima, Satoshi Tanaka, Makoto Osanai, Koichi Hirata, Norimasa Sawada
  • Journal Title: Virchows Arch Volume: 469 Pages: 417-426
  • DOI: 10.1007/s00428-016-1984-z
  • Peer Reviewed
• [Journal Article] Claudins in cancer: bench to bedside. (2016)
  • Author(s): Osanai M, Takasawa A, Murata M, Sawada N.
  • Journal Title: Pflugers Ach Volume: 469(1) Pages: 55-67
  • DOI: 10.3892/or.2016.5072
  • Peer Reviewed
• [Journal Article] Nuclear localization of tricellulin promotes the oncogenic property of pancreatic cancer. (2016)
  • Author(s): Takasawa A, Murata M, Takasawa K, Ono Y, Osanai M, Tanaka S, Nojima M, Kono T, Hirata K, Kojima T, Sawada N.
  • Journal Title: Sci Rep Volume: 19(6) Pages: 33582-33582
  • DOI: 10.1038/srep33852
  • Peer Reviewed